Discovery of Gene Expression Signatures in Cancer Stroma

描述(申请人提供)：越来越多的研究表明，间质在癌症的维持和生长中起着重要作用，但对肿瘤中存在的不同类型的间质知之甚少。此外，由于肿瘤内的间质细胞被认为是“正常”的，而且与肿瘤细胞相比，遗传不稳定，因此不太可能对治疗产生获得性耐药，因此，肿瘤间质可能是定向治疗的良好靶点。肿瘤间质含有多种间充质细胞类型，包括成纤维细胞、肌成纤维细胞、内皮细胞和脂肪细胞。这些谱系的表达谱只是部分已知的，很可能存在几种目前无法识别的这些细胞亚型。我们假设，在特定的肿瘤组(如乳腺癌)中，存在以不同方式影响肿瘤生长的不同类型的间质。我们进一步假设，软组织肿瘤(STT)被认为来自不同的间质前体，可以作为不同间质类型的发现工具。软组织肿瘤(包括恶性变种肉瘤)来源于多种正常结缔组织细胞，可被认为是不同亚型间充质细胞的克隆性产物，如成纤维细胞和肌成纤维细胞，以及其他尚未发现的间质成分。我们建议在全基因组搜索中使用STT作为“发现工具”，以发现一组新的标记，这些标记识别不同类型的肿瘤间质，并识别这些类型的间质源自的正常结缔组织对应物。通过识别区分不同STT的基因子集，我们的项目将研究这些基因集如何区分具有不同间质类型的癌症。在两个不同的研究中，我们已经证明这是可行的，事实上，不同的间质类型与不同的临床结果相关。在拟议的项目中，我们将对更多的STT进行基因表达谱分析，以发现更多新的癌症间质类型。随后，我们将验证和扩展我们在组织微阵列上的发现，该微阵列包含数百个来自已知临床随访患者的几种癌症的样本。最后，我们将确定与癌症和间质细胞之间的“串扰”有关的上皮-间质基因对。这项拨款提案旨在扩大我们对癌症间质反应的理解，并通过寻找参与这种反应的新基因和途径，确定肿瘤微环境靶向治疗的新靶点。除了将它们用作预后标记物外，我们认为潜在的治疗靶点也可能在这组基因中被发现，特别是那些涉及癌症和间质细胞之间的“串扰”的基因。我们的研究还将有助于确定哪些癌症亚型对这些间质靶向治疗有反应。事实上，不同的癌症共享这些靶点的表达，这意味着患有各种肿瘤的大群患者可能会受益。公共卫生相关性：这项拨款提案旨在扩大我们对癌症间质反应的理解，并通过寻找参与这种反应的新基因和途径，确定肿瘤微环境靶向治疗的新靶点。除了将它们用作预后标记物外，我们认为潜在的治疗靶点也可能在这组基因中被发现，特别是那些涉及癌症和间质细胞之间的“串扰”的基因。事实上，不同的癌症共享这些靶点的表达，这意味着患有各种肿瘤的大群患者可能会受益。

DESCRIPTION (provided by applicant): A growing body of research has shown that the stroma plays a significant role in the maintenance and growth of carcinomas, but little is known about the different types of stroma that exist in tumors. Moreover, as the stromal cells within the tumor are thought to be "normal" and less genetically labile than the neoplastic cells, development of acquired resistance to therapy is thought to be less likely and as such, the tumor stroma may be an excellent target for directed therapy. Tumor stroma contains a variety of mesenchymal cell types that include fibroblasts, myofibroblasts, endothelial cells, and adipocytes. The expression profiles of these lineages are only partially known and it is likely that several currently unrecognized subtypes of these cells exist. We hypothesize that within a particular group of tumors (e.g. breast carcinoma) there exist distinct types of stroma that affect tumor growth in different ways. We further hypothesize that soft tissue tumors (STTs), thought to be derived from different stromal precursors, could function as discovery tools for the various stroma types. Soft tissue tumors (including the malignant variants called sarcomas) are derived from a wide variety of normal connective tissue cells and can be thought of as clonal outgrowths of different subtypes of mesenchymal cells such as fibroblasts and myofibroblasts, and other, as yet undiscovered, stromal components. We propose to use STTs as "discovery tools" in a genome-wide search to discover groups of novel markers that identify distinct types of tumor stroma and that recognize the normal connective tissue counterparts from which these types of stroma are derived. By identifying subsets of genes that distinguish different STT, our project will examine how these gene sets can differentiate between carcinomas with distinct stroma types. In two separate studies we have shown that this is feasible and that in fact the different stroma types are associated with different clinical outcomes. In the proposed project, we will perform gene expression profiling on additional STTs to discover further new types of carcinoma stroma. Subsequently, we will verify and extend our findings on tissue microarrays containing hundreds of specimens of several carcinomas from patients with known clinical follow-up. Finally, we will identify epithelial-stromal gene-pairs involved in the "cross-talk" between cancer and stromal cells. This grant proposal aims to expand our understanding of stromal responses to cancer and, by finding new genes and pathways involved in this response, identify new targets for tumor microenvironment-targeted therapy. In addition to their use as prognostic markers, we believe that potential therapeutic targets may also be discovered in the group of genes, especially those involved in "cross-talk" between cancer and stromal cells. Our studies will also help identify which subsets of cancers would respond to these stroma-targeted therapies. The fact that different carcinomas share expression of these targets would mean that large groups of patients suffering from a variety of tumors could benefit. PUBLIC HEALTH RELEVANCE: This grant proposal aims to expand our understanding of stromal responses to cancer and, by finding new genes and pathways involved in this response, identify new targets for tumor microenvironment-targeted therapy. In addition to their use as prognostic markers, we believe that potential therapeutic targets may also be discovered in the group of genes, especially those involved in "cross-talk" between cancer and stromal cells. The fact that different carcinomas share expression of these targets would mean that large groups of patients suffering from a variety of tumors could benefit.